Program Director/Principal Investigator (Last, First, Middle): Jones, Clinton, J PROJECT SUMMARY (See instructions): Following infection of mice with herpes simplex virus 1 (HSV-1), neurons in brainstem and trigeminal ganglia (TG) are primary sites for latency. Reactivation from latency consistently occurs in these same anatomical sites following explant of tissue or heat shock induced stress. In contrast to productive infection, the latency associated transcript (LAT) is the only viral gene abundantly expressed in latently infected neurons. Recent studies demonstrated that ?-catenin and the ?-catenin coactivator, High-Mobility Group AT?Hook 1 protein (HMGA1) were detected in TG neurons of mice latently infected with HSV-1 but not TG neurons of uninfected mice. In contrast, the Wnt antagonist, dickopf 1 (DKK-1) protein, which has been reported to cause neuro-degeneration, was induced during explant-induced reactivation from latency. Expression of LAT in mouse neuroblastoma cells stabilized ?-catenin protein expression, which correlated with enhanced cell survival. Since the canonical Wnt/?-catenin signaling pathway promotes neurogenesis and neuronal survival, we hypothesize that the Wnt/?-catenin signaling pathway cooperates with LAT to regulate the HSV- 1 latency-reactivation cycle. Studies in Specific Aim 1 will compare ?-catenin, HMGA1, and DKK-1 expression in brainstem and TG neurons during the latency-reactivation cycle following infection with a LAT null mutant virus or wild-type HSV-1. Small molecules that regulate the Wnt/?-catenin signaling pathway will also be examined for their effects on reactivation from latency. Studies in Specific Aim 2 will identify LAT functions important for mediating ?-catenin expression and examine how LAT and ?-catenin cooperate to interfere with apoptosis in neuroblastoma cells and mice. These studies will provide insight into the mechanism by which the Wnt/?-catenin signaling pathway regulates the HSV-1 latency-reactivation cycle. The HSV-1 latency-reactivation cycle is responsible for encephalitis, recurrent eye disease, including stromal keratitis, and genital lesions in humans. At this point, there are no HSV-1 vaccines or therapeutic strategies that specifically interfere with the reactivation from latency. Although LAT is an important regulator of the latency-reactivation cycle, cellular factors that regulate the Wnt/?-catenin signaling pathway may mediate crucial steps during the latency-reactivation cycle. RELEVANCE (See instructions): Recurrent herpes simplex virus 1 (HSV-1) infections occur because the virus can establish, maintain, and reactivate from latency. LAT is the only viral gene abundantly expressed in latently infected neurons. Studies in this proposal will examine the role that the Wnt/?-catenin signaling pathway cooperates with LAT to regulate the latency-reactivation cycle.